Nitrosated and nitrosylated α-adrenergic receptor antagonist compounds, compositions and their uses

ABSTRACT

Disclosed are nitrosated and nitrosylated α-adrenergic receptor antagonists, compositions of an α-adrenergic receptor antagonist (α-antagonist), which can optionally be substituted with at least one NO or NO 2  moiety, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO - ), or as the neutral species, nitric oxide (NO); and uses for each of them in treating human male impotence or erectile dysfunction.

FIELD OF THE INVENTION

This invention generally relates to α-adrenergic receptor antagonists,compositions containing them and their use in treating human maleimpotence.

BACKGROUND OF THE INVENTION

Erectile dysfunction or impotence is a widespread disorder that isthought to affect about ten to fifeteen percent of adult men. Somepharmacological methods of treatment are available. Such methods,however, have not proven to be highly satisfactory or withoutpotentially severe side-effects. Papaverine is now widely used to treatimpotence, although papaverine is ineffective in overcoming impotencedue, at least in part, to severe atherosclerosis. Papaverine iseffective in cases where the dysfunction is psychogenic or neurogenicand severe atherosclerosis is not involved. Injection of papaverine, asmooth muscle relaxant, or phenoxybenzamine, a non-specific antagonistand hypotensive, into a corpus cavernosum has been found to cause anerection sufficient for vaginal penetration however, these treatmentsare not without the serious and often painful side effect of priapisim.Also, in cases where severe atherosclerosis is not a cause of thedysfunction, intracavernosal injection of phentolamine, an α-adrenergicantagonist, is used. As an alternative or, in some cases, blockade,prostaglandin E1 (PGE1) has been administered via intracavernosalinjection. A major side effect frequently associated with intracorprallydelivered PGE1 is penile pain and burning. Thus, there is a need fortreatments of human male impotence without the undesirable side effectsof those agents currently used.

SUMMARY OF THE INVENTION

Nitric oxide (NO) and NO donors have been recognized as mediators ofnonvascular smooth muscle relaxation. This effect includes the dilationof the corpus cavernosum smooth muscle, an event involved in the penileerection process. However, the effects of such compounds together withα-adrenergic receptor antagonists or the modifications of α-adrenergicreceptor antagonists to be directly or indirectly linked with a nitricoxide adduct have not been investigated.

In the process of arriving at the present invention it was recognizedthat the risk of toxicities and adverse effects that are associated withhigh doses of α-adrenergic receptor antagonists can be avoided by theuse of such α-adrenergic receptor antagonists when nitrosated ornitrosylated or when administered in conjunction with compounds thatdonate, release or transfer nitric oxide. Such toxicities and adverseeffects include postural hypotension, reflex tachycardia and otherarrythmias, syncope and, with respect to the ergot alkaloids, nausea andvomiting and, upon prolonged or excessive administration, vascularinsufficiency and gangrene of the extremities. The α-adrenergic receptorantagonists and compounds that donate, release or transfer nitric oxidework together to permit the same efficacy with lower doses of theα-adrenergic receptor antagonists.

Accordingly, in one aspect the invention provides novel nitrosated andnitrosylated α-adrenergic receptor antagonists (NO_(n) -α-antagonists)wherein n is 1 or 2. The α-adrenergic antagonist can be nitrosylated ornitrosated through sites such as oxygen (hydroxyl condensation), sulfur(sulfhydryl condensation), carbon and nitrogen. The invention alsoprovides compositions comprising such compounds in a pharmaceuticallyacceptable carrier. pharmaceutically acceptable carrier.

In another aspect the invention provides a composition comprising atherapeutically effective amount of an α-adrenergic receptor antagonist(α-antagonist), which can optionally be substituted with at least one NOor NO₂ moiety, and a compound that donates, transfers or releases nitricoxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻),or as the neutral species, nitric oxide (NO), preferably in a one toten fold molar excess. The invention also provides compositionscomprising such compounds in a pharmaceutically acceptable carrier. Theα-adrenergic receptor antagonist used in the composition can be thosedescribed above and others which are known and can alternatively be suchα-antagonists which have been nitrosated or nitrosylated in accordancewith the invention.

In another aspect, the invention provides a method for treating maleimpotence in humans which comprises administering to an individual inneed thereof a therapeutically effective amount of a nitrosated ornitrosylated α-antagonist.

In another aspect, the invention provides a method for treating maleimpotence in humans which comprises administering to an individual inneed thereof a composition comprising a therapeutically effective amountof an α-antagonist which can optionally be substituted with at least oneNO or NO₂ moiety, and a compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO⁻), or as the neutral species, nitric oxide (NO). The α-antagonistor α-antagonist directly or indirectly linked to at least one NO or NO₂group, and nitric oxide donor can be administered separately or ascomponents of the same composition.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the percent peak erectile response in vivo compared to thatproduced by 150μl of pap/phent/PGE1 (30 mg/ml: 1 mg/ml: 10 μg/ml) in theanesthetized rabbit following the intracavernosal injection of 150 μl ofyohimbine (150 μg, 500 μg), Example 1 (500 μg), and a combination ofyohimbine (150 μg) and Example 1 (500 μg). The ordinate is the percentresponse of intracavernosal pressure relative to that produced bypap/phent/PGE1 and the abscissa indicates the various drugs given.

FIG. 2 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavemosal administration of yohimbine (150μg, 500 μg), Example 1 (500 μg), and a combination of yohimbine (150 μg)and Example 1 (500 μg). The ordinate indicates the various drugs givenand the abscissa is the duration in minutes.

FIG. 3 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml: 1 mg/ml: 10 μg/ml) inthe anesthetized rabbit following the intracavemosal injection of 150 μlof yohimbine (150 μg, 500 μg and 1 mg) and Example 2 (500 μg, 1 mg). Theordinate is the percent response of intracavernosal pressure relative tothat produced by pap/phent/PGE1 and the abscissa indicates the variousdoses of yohimbine and Example 2 given.

FIG. 4 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg and 1 mg) and Example 2 (500 μg and 1 mg). The ordinateindicates the various doses of yohimbine and Example 2 given and theabscissa is the duration in minutes.

FIG. 5A shows the effects of intracavernosal injections of Example 2(500 μg) on systemic blood pressure in the anesthetized rabbit. FIG. 5Bshows the effects of intracavernosal injections of the standard mixtureof pap/phent/PGE1 on systemic blood pressure in the anesthetized rabbit.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein refers to branched or straightchain alkyl groups comprising one to ten carbon atoms, including methyl,ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.

The term "alkoxy" as used herein refers to R₅₀ O-wherein R₅₀ is loweralkyl as defined above. Representative examples of alkoxy groups includemethoxy, ethoxy, t-butoxy and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group aspreviously defined appended to an alkyl group as previously defined.Examples of alkoxyalkyl include, but are not limited to, methoxymethyl,methoxyethyl, isopropoxymethyl and the like.

The term "hydroxy" as used herein refers to --OH.

The term "hydroxyalkyl" as used herein refers to a hydroxy group aspreviously defined appended to an alkyl group as previously defined.

The term "alkenyl" as used herein refers to a branched or straight chainC₂ -C₁₀ hydrocarbon which also comprises one or more carbon-carbondouble bonds.

The term "amino" as used herein refers to --NH₂.

The term "nitrate" as used herein refers to --O--NO₂.

The term "alkylamino" as used herein refers to R₁₁ NH-- wherein R₁₁ is alower alkyl group, for example, methylamino, ethylamino, butylamino, andthe like.

The term "dialkylamino" as used herein refers to R₁₂ R₁₃ N-- wherein R₂and R₁₃ are independently selected from lower alkyl, for exampledimethylamino, diethylamino, methyl propylamino and the like.

The term "nitro" as used herein refers to the group --NO₂ and"nitrosated" refers to compounds that have been substituted therewith.

The term "nitroso" as used herein refers to the group --NO and"nitrosylated" refers to compounds that have been substituted therewith.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclicring system having one or two aromatic rings including, but not limitedto, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and thelike. Aryl groups (including bicyclic aryl groups) can be unsubstitutedor substituted with one, two or three substituents independentlyselected from loweralkyl, haloalkyl, alkoxy, amino, alkylamino,dialkylamino, hydroxy, halo, and nitro. In addition, substituted arylgroups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" as used herein refers to a lower alkyl radical towhich is appended an aryl group . Representative arylalkyl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl and the like.

The term "cycloalkyl" as used herein refers to an alicyclic groupcomprising from 3 to 7 carbon atoms including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "halogen" or "halo" as used herein refers to I, Br, Cl, or F.The term "haloalkyl" as used herein refers to a lower alkyl radical, asdefined above, bearing at least one halogen substituent, for example,chloromethyl, fluoroethyl or trifluoromethyl and the like.

The term "heteroaryl" as used herein refers to a mono- or bi- cyclicring system containing one or two aromatic rings and containing at leastone nitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroarylgroups (including bicyclic heteroaryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro. Examples of heteroaryl groups include but arenot limited to pyridine, pyrazine, pyrimidine, pyridazine, pyrazole,triazole, thiazole, isothiazole, benzothiazole, benzoxazole,thiadiazole, oxazole, pyrrole, imidazole and isoxazole.

The term "heterocyclic ring" refers to any 3-, 4-, 5-, 6-, or 7-memberednonaromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom which is bonded to an atom which is not part of theheterocyclic ring.

The term "arylheterocyclic ring" as used herein refers to a bi- ortricyclic ring comprised of an aryl ring as previously defined appendedvia two adjacent carbons of the aryl group to a heterocyclic ring aspreviously defined.

The term "heterocyclic compounds" herein refers to mono and polycycliccompounds containing at least one heteroaryl or heterocyclic ring.

Compounds of the invention which have one or more asymmetric carbonatoms may exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It is to be understood that the present invention anticipatesand includes within its scope all such isomers and mixtures thereof.

The α-adrenergic receptor antagonists that are nitrosated ornitrosylated in accordance with the invention and/or are included in thecompositions of the invention can be any of those known to the art,including those exemplified below. Structurally, the α-antagonists cangenerally be categorized as haloalkylamines, imidazolines, quinozolines,indole derivatives, phenoxypropanolamines, alcohols, alkaloids, amines,piperizines and piperidines.

The first group of α-antagonists are the haloalkylamines that block α₁ -and α₂ -adrenergic receptors irreversibly. Included in this group are,for example, phenoxybenzamine and dibenamine. Phenoxybenzamine is usedin the treatment of pheochromocytomas, tumors of the adrenal medulla andsympathetic neurons that secrete catecholamines into the circulation. Itcontrols episodes of severe hypertension and minimizes other adverseeffects of catecholamines such as contraction of plasma volume andinjury of the myocardium.

Another group of such α-antagonists are the imidazolines. These includephentolamine and tolazoline. Phentolamine has similar affinity for α₁and α₂ receptors. Phentolamine is used in short-term control ofhypertension in patients with pheochromocytoma and direct,intracavernous injection of phentolamine (usually in combination withpapaverine) has been proposed as a treatment for male sexualdysfunction. Tolazoline is used in the treatment of persistent pulmonaryhypertension in neonates. Others include idazoxan, deriglidole, RX821002, BRL 44408 and BRL 44409 (see Eur. J. Pharm., 168:381, 1989)

Another group of α-antagonist compounds that are contemplated are thequinazolines. These include, for example, prazosine, a very potent andselective a₁ adrenergic antagonist, terazosin, doxazosin, alfuzosin,bunazosin, ketanserin, trimazosin and abanoquil. This group of compoundsis principally used in the treatment of primary systemic hypertensionand also in the treatment of congestive heart failure.

Another class of such α-adrenergic blocking agents are indolederivatives. These include, for example, carvedilol and BAM 1303.

Another class of such α-adrenergic blocking agents are alcohols. Theseinclude, for example, labetelol and ifenprodil.

Another class of such α-adrenergic blocking agents are alkaloids. Theseinclude, for example, "ergotoxine," which is a mixture of threealkaloids, i.e., ergocornine, ergocristine and ergocryptine. Bothnatural and dihydrogenated peptide alkaloids produce α-adrenergicblockade. The principal uses are to stimulate contraction of the uteruspostpartum and to relieve the pain of migraine headaches. Another indolealkaloid is yohimbine. This compound is a competitive antagonist that isselective for α₂ -adrenergic receptors. In humans, it has been observedto increase blood pressure and heart rate and has been used in thetreatment of male sexual dysfunction. Other alkaloid α-blockers includerauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine,akuammigine, β-yohimbine, yohimbol, pseudoyohimbine andepi-3α-cyohimbine.

Another class of such α-adrenergic blocking agents are amines. Theseinclude, for example, tamsulosin, benoxathian, atipamezole, BE 2254, WB4101 and HU-723.

Another class of such α-adrenergic blocking agents are piperizines.These include, for example, naftopil and saterinone.

Another class of such α-adrenergic blocking agents are piperidines.These include, for example, haloperidol.

Each of the above contemplated α-antagonists is described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (8th Edition), McGraw-Hill, 1990, Pgs. 221-243.

One embodiment of this aspect includes substituted compounds of theformula: ##STR1## wherein, R_(a) is selected from hydrogen or alkoxy;

R_(b) is selected from ##STR2## wherein a is an integer of 2 or 3;

R_(c) is selected from heteroaryl, heterocyclic ring, lower alkyl,hydroxyalkyl, and arylheterocyclic ring;

D is selected from (i) --NO; (ii) --NO₂ ; (iii) --C(R_(d))--O--C(O)--Y--C(R_(e))(R_(f))!_(p) --T--Q in which R_(d) is hydrogen, lower alkyl,cycloalkyl, aryl or heteroaryl, Y is oxygen, sulfur, or NR_(i) in whichR_(i) is hydrogen or lower alkyl, R_(e) and R_(f) are independentlyselected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl,arylalkyl, alkylamino, dialkylamino or taken together are carbonyl,cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6, T is acovalent bond, oxygen, sulfur or nitrogen and Q is selected from --NO or--NO₂ ; (iv)--(CO)--T¹ -- C(R_(e))(R_(f))!_(p) --T² --Q wherein T¹ andT² are independently selected from T and R_(e), R_(f), p, and T aredefined as above; (v) --C(O)--T C(R_(y))(R_(z))!_(p) wherein R_(y) andR_(z) are independently selected from --T¹ -- C(R_(e))(R_(f))!_(p) --G--C(R_(e))(R_(f))!_(p) --T² --Q wherein G is (i) a covalent bond; (ii)--T--C(O)--; (iii) --C(O)--T; and wherein R_(d), R_(e), R_(f), p, Q andT are as defined above.

Another embodiment of this aspect is substituted compounds of theformula: ##STR3## wherein, R_(g) is selected from: ##STR4## wherein D₁is selected from hydrogen or D wherein D is as defined above.

Another embodiment of this aspect includes substituted compounds of theformula: ##STR5## wherein R_(h) is selected from hydrogen,--C(O)--OR_(d) or --C(O)--X wherein X is (1) --Y-- C(R_(e))(R_(f))!_(p)--G-- C(R_(e))(R_(f))!_(p) --T--Q; wherein G is (i) a covalent bond;(ii) --T--C(O)--; (iii) --C(O)--T; (iv) --C(Y--C(O)--R_(m))-- whereinR_(m) is heteroaryl or heterocyclic ring; and in which Y, R_(d), R_(e),R_(f), p, Q and T are as defined above; or (2) ##STR6## in which W is aheterocyclic ring or NR_(i) R'_(i) wherein R_(i) and R'_(i) areindependently selected from lower alkyl, aryl or alkenyl; and wherein Rjis selected from --D or --(O)CR_(d) wherein D and R_(d) are as definedabove.

Another embodiment of this aspect includes substituted compounds of theformula: ##STR7## wherein, A₁ is oxygen or methylene and X and R_(j) areas defined above.

Another embodiment of this aspect includes substituted compounds of theformula: ##STR8## wherein, R_(k) is selected from hydrogen or loweralkyl;

and wherein R_(l) is selected from: ##STR9## wherein b is an integer of0 or 1; D₁ is as defined above; and R_(n) is selected from: ##STR10##wherein A₂ is oxygen or sulfur.

Another embodiment of this aspect includes substituted compounds of theformula: ##STR11## wherein R_(o) is selected from: ##STR12## and R_(p)is selected from: ##STR13## and R_(k) and D are as defined above.

Another embodiment of this aspect includes substituted compounds of theformula: ##STR14## wherein R_(d), T and D are defined as above.

The present invention also relates to processes for preparing thecompounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) and tothe intermediates useful in such processes.

Some of the nitrosated and nitrosylated α-antagonists of the presentinvention may be synthesized as shown in reaction Schemes I throughXVIII presented below, in which R_(a), R_(b), R_(c), R_(d), R_(e),R_(f), R_(g), R_(h), R_(i), R_(i), R_(j), R_(k), R_(l), R_(m), R_(n),R_(o), R_(p), A₁, A₂, a, n, W and X are as defined above or as depictedin the reaction schemes for formulas I, II, III, IV, V, VI or VII. P¹ isan oxygen protecting group and P² is a sulfur protecting group. Thereactions are performed in solvents appropriate to the reagents andmaterials employed are suitable for the transformations being effected.It is understood by those skilled in the art of organic synthesis thatthe functionality present in the molecule must be consistent with thechemical transformation proposed. This will, on occasion, necessitatejudgment by the routineer as to the order of synthetic steps, protectinggroups required, and deprotection conditions. Substituents on thestarting materials may be incompatible with some of the reactionconditions required in some of the methods described, but alternativemethods and substituents compatible with the reaction conditions will bereadily apparent to skilled practitioners in the art. The use of sulfurand oxygen protecting groups is well known in the art for protectingthiol and alcohol groups against undesirable reactions during asynthetic procedure and many such protecting groups are known, c.f., T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, New York (1991).

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Nitroso compounds of formula (I) wherein R_(a), R_(b), R_(e), R_(f), andp are as defined above and an O-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme I. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula 2 wherein p, R_(e) and R_(f) are as defined aboveby reaction with an appropriate protected alcohol containing activatedacylating agent wherein P¹ is as defined above. Preferred methods forthe formation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the protected alcohol-containingacid. Preferred protecting groups for the alcohol moiety are silylethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosium tetrafluoroborate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of the formula IA. ##STR15##

Nitroso compounds of formula (I) wherein R_(a), R_(b), R_(e), R_(f), andp are defined as above and an S-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme II. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula 3 wherein p, R_(e) and R_(f) are defined as aboveby reaction with an appropriate protected thiol-containing activatedacylating agent wherein P² is as defined above. Preferred methods forthe formation of amides are reacting the amine with the preformed acidchloride or symmetrical anhydride of the protected thiol containingacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IB.Alternatively, treatment of compound 3 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IB.##STR16##

Nitro compounds of formula (I) wherein R_(a), R_(b), R_(e), R_(f), and pare defined as above and an O-nitrosated amide is representative of theD group as defined above may be prepared according to Scheme III. Theamine group of the quinazoline of the formula 1 is converted to theamide of the formula IC wherein p, R_(e) and R_(f) are defined as aboveby reaction with an appropriate nitrate containing activated acylatingagent. Preferred methods for the formation of amides are reacting theamine with the preformed acid chloride or symmetrical anhydride of thenitrate containing acid to afford the compound of the formula IC.##STR17##

Nitroso compounds of formula (II) wherein R_(e), R_(f), R_(g), and p aredefined as above and an O-nitrosylated acyl imidazoline isrepresentative of the D group as defined above may be prepared accordingto Scheme IV. The imidazoline group of the formula 4 is converted to theacyl imidazoline of the formula 5 wherein p, R_(e) and R_(f) are definedas above by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P¹ is as defined above. Preferredmethods for the formation of acyl imidazolines are reacting theimidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected alcohol containing acid. Preferred protecting groups forthe alcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIA. ##STR18##

Nitroso compounds of formula (II) wherein R_(e), R_(f), R_(g), and p aredefined as above and an S-nitrosylated acyl imidazoline isrepresentative of the D group as defined above may be prepared accordingto Scheme V. The imidazoline group of the formula 4 is converted to theacyl imidazoline of the formula 6 wherein p, R_(e) and R_(f) are definedas above by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P² is as defined above. Preferredmethods for the formation of acyl imidazolines are reacting theimidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected thiol containing acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF or acetonitrile with or without an amine base such aspyridine or triethylamine affords the compound of the formula IIB.Alternatively, treatment of compound 6 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IIB.##STR19##

Nitro compounds of formula (II) wherein R_(e), R_(f), R_(g), and p aredefined as above and on O-nitrosated acyl imidazoline is representativeof the D group as defined above may be prepared according to Scheme VI.The imidazoline group of the formula 4 is converted to the acylimidazoline of the formula IIC wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate nitrate containing activatedacylating agent. Preferred methods for the formation of acylimidazolines are reacting the amine with the preformed acid chloride orsymmetrical anhydride of the nitrate containing acid to afford thecompound of the formula IIC. ##STR20##

Nitroso compounds of formula (III) wherein R_(e), R_(f), R_(h), R_(j),and p are defined as above and an O-nitrosylated ester is representativeof the D group as defined above may be prepared according to Scheme VII.The alcohol group of formula 7 is converted to the ester of formula 8wherein p, R_(e) and R_(f) are defined as above by reaction with anappropriate protected alcohol containing activated acylating agentwherein P¹ is as defined above. Preferred methods for the formation ofesters are reacting the alcohol with the preformed acid chloride orsymmetrical anhydride of the protected alcohol containing acid.Preferred protecting groups for the alcohol moiety are silyl ethers suchas a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removingsilyl ether protecting groups) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,or nitrosium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIIA. ##STR21##

Nitroso compounds of formula (III) wherein R_(e), R_(f), R_(h), R_(j),and p are defined as above and an S-nitrosylated ester is representativeof the D group as defined above may be prepared according to SchemeVIII. The alcohol group of the formula 7 is converted to the ester ofthe formula 9 wherein p, R_(e) and R_(f) are defined as above byreaction with an appropriate protected thiol containing activatedacylating agent wherein P² is as defined above. Preferred methods forthe formation of esters are reacting the alcohol with the preformed acidchloride or symmetrical anhydride of the protected thiol containingacid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IIIB.Alternatively, treatment of compound 9 with a stoichiometric quantity ofsodium nitrite in aqueous acid affords the compound of the formula IIIB.##STR22##

Nitro compounds of formula (II) wherein R_(e), R_(f), R_(h), R_(j), andp are defined as above and an O-nitrosated ester is representative ofthe D group as defined above may be prepared according to Scheme IX. Thealcohol group of the formula 7 is converted to the ester of the formulaIIIC wherein p, R_(e) and R_(f) are defined as above by reaction with anappropriate nitrate containing activated acylating agent. Preferredmethods for the formation of esters are reacting the alcohol with thepreformed acid chloride or symmetrical anhydride of the nitratecontaining acid to afford a compound of the formula IIIC. ##STR23##

Nitroso compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h),R_(j), and p are defined as above and an O-nitrosylated ester isrepresentative of the X group as defined above may be prepared accordingto Scheme X. An acid of the formula 10 is converted into the ester ofthe formula 11 wherein p, R_(e), and R_(f) are defined as above byreaction with an appropriate monoprotected diol. Preferred methods forthe preparation of esters are initially forming the mixed anhydride viareaction of 10 with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as dichloromethane, diethylether, or THF.The mixed anhydride is then reacted with the monoprotected alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamine pyridine. Alternatively, the acid 10 may be firstconverted to the acid chloride be treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the monoprotected alcohol preferably in the presence of acondensation catalyst such as 4-dimethylamino- pyridine and a tertiaryamine base such as triethyl amine to afford the ester 11. Alternatively,the acid 10 and monoprotected diol may be coupled to afford 11 bytreatment with a dehydration agent such as dicyclohexylcarbodiimide.Preferred protecting groups for the alcohol moiety are silyl ethers suchas a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removingsilyl ether protecting groups) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,or nitrosium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile affords the compound of theformula IVA. ##STR24##

Nitroso compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h),R_(j), and p are defined as above and an S-nitrosylated ester isrepresentative of the X group as defined above may be prepared accordingto Scheme XI. An acid of the formula 10 is converted into the ester ofthe formula 12 wherein p, R_(e), and R_(f) are defined as above and aS-nitrosylated ester is representative of the X group as defined aboveby reaction with an appropriate protected thiol containing alcohol.Preferred methods for the preparation of esters are initially formingthe mixed anhydride via reaction of 10 with a chloroformate such asisobutylchloroformate in the presence of a non nucleophilic base such astriethylamine in an anhydrous inert solvent such as diethylether or THF.The mixed anhydride is then reacted with the thiol containing alcoholpreferably in the presence of a condensation catalyst such as4-dimethylaminopyridine. Alternatively, the acid 10 may be firstconverted to the acid chloride be treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the monoprotected thiol preferably in the presence of acondensation catalyst such as 4-dimethylamine pyridine and a tertiaryamine base such as triethyl amine to afford the ester 12. Alternatively,the acid and thiol containing alcohol may be coupled to afford 12 bytreatment with a dehydration agent such as dicyclohexylcarbodiimide.Preferred protecting groups for the thiol moiety are as a thioester suchas a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamatesuch as N-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thiolesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylnethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile with or without an amine base such aspyridine or triethylamine affords the compound of the formula IVB.Alternatively, treatment of compound 12 with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaIVB. ##STR25##

Nitro compounds of formula (IV) wherein A₁, R_(e), R_(f), R_(h), R_(j),and p are defined as above and an O-nitrosated ester is representativeof the X group as defined above may be prepared according to Scheme XII.An acid of the formula 10 is converted into the ester of the formula IVCwherein p, R_(e), and R_(f) are defined as above by reaction with anappropriatenitrate containing alcohol. Preferred methods for thepreparation of esters are initially forming the mixed anhydride viareaction of 10 with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as dichloromethane, diethylether, or THF.The mixed anhydride is then reacted with the nitrate containing alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamino-pyridine. Alternatively, the acid 10 may be firstconverted to the acid chloride be treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the nitrate containing alcohol preferably in the presence of acondensation catalyst such as 4-dimethylaminopyridine and a tertiaryamine base such as triethyl amine to afford the a compound of theformula IVC. Alternatively, the acid 10 and nitrate containing alcoholmay be coupled to afford a compound of the formula IVC by treatment witha dehydration agent such as dicyclohexylcarbodiimide. ##STR26##

Nitroso compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(l),R_(n), and p are defined as above and an O-nitrosylated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XIII. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula 14 wherein p,R_(e), and R_(f), are defined as above by reaction with an appropriateprotected alcohol containing chloromethyl acyl derivative wherein P¹ isas defined above. Preferred methods for the formation of N-acyloxyalkylamines are reacting the amine with the preformed chloromethylacyloxyalkyl derivative of the protected alcohol. Preferred protectinggroups for the alcohol moiety are silyl ethers such as a triethylsilylor a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVA. ##STR27##

Nitroso compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(k),R_(n), and p are defined as above and an S-nitrosylated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XIV. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula 15 wherein p,R_(e), and R_(f), are defined as above by reaction with an appropriateprotected thiol containing chloromethyl acyl derivative wherein P² is asdefined above. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a tetrahydropyranyl thioether. Deprotection of the thiol moiety(triphenylphosphine in water and sodium borohydride are preferredmethods for reducing disulfide groups while aqueous base is typicallyutilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates andmercuric trifluoroacetate or silver nitrate are used to remove atetrahydropyranyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula VB.##STR28##

Nitro compounds of formula (V) wherein R_(e), R_(f), R_(k), R_(l),R_(n), and p are defined as above and an O-nitrosated N-acyloxyalkylamine is representative of the D group as defined above may be preparedaccording to Scheme XV. The amine group of the compound of the formula13 is converted to the N-acyloxyalkyl amine of the formula VC wherein p,R_(e), and R_(f) are defined as above by reaction with an appropriatenitrate containing chloromethyl acyl derivative. Preferred methods forthe formation of N-acyloxyalkyl amines are reacting the amine with thepreformed chloromethyl acyloxyalkyl derivative of the nitrate containingderivative to afford the compound of the formula VC. ##STR29##

Nitroso compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an O-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVI.The amine group of the dihydropyridine of the formula 14 is converted tothe amide of the formula 15 wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate protected alcohol containingactivated acylating agent wherein P¹ is as defined above. Preferredmethods for the formation of amides are reacting the amine with thepreformed acid chloride or symmetrical anhydride of the protectedalcohol containing acid. Preferred protecting groups for the alcoholmoiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVIIA. ##STR30##

Nitroso compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an S-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVII.The amine group of the dihydropyridine of the formula 14 is converted tothe amide of the formula 16 wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate protected thiol containingactivated acylating agent wherein P² is as defined above. Preferredmethods for the formation of amides are reacting the amine with thepreformed acid chloride or symmetrical anhydride of the protected thiolcontaining acid. Preferred protecting groups for the thiol moiety are asa thioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula VIIB.Alternatively, treatment of compound 16 with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaVIIB. ##STR31##

Nitro compounds of formula (VII) wherein R_(d), R_(e), R_(f), T, and pare defined as above and an O-nitrosated amide is representative of theD group as defined above may be prepared according to Scheme XVIII. Theamine group of the dihydropyridine of the formula 14 is converted to theamide of the formula VIIC wherein p, R_(e) and R_(f) are defined asabove by reaction with an appropriate nitrate containing activatedacylating agent. Preferred methods for the formation of amides arereacting the amine with the preformed acid chloride or symmetricalanhydride of the nitrate containing acid to afford the compound of theformula VIIC. ##STR32##

As noted above, another aspect the invention provides a compositioncomprising a therapeutically effective amount of an α-adrenergicreceptor antagonist (α-antagonist), which can optionally be substitutedwith at least one NO or NO₂ moiety, and a compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutral species, nitricoxide (NO).

Another embodiment of this aspect is one where the α-blocker is notsubstituted with at least one NO or NO₂ moiety. Additional α-blockersthat are suitable for this embodiment include amines, such as tedisamil,mirtazipine, setiptiline, reboxitine and delequamine; amides, such asindoramin and SB 216469; piperizines, such as SL 89.0591, ARC 239,urapidil, 5-methylurapidil and monatepil. Indoramin is a selective,competitive α₁ -antagonist that has been used for the treatment ofhypertension. Urapidil is also known to be a selective α₁ -adrenergicantagonist that has a hypotensive effect in humans.

The compounds that donate, transfer or release nitric oxide can be anyof those known to the art, including those mentioned and/or exemplifiedbelow.

Nitrogen monoxide can exist in three forms: NO⁻ (nitroxyl), NO (nitricoxide) and NO⁺ (nitrosonium). NO is a highly reactive short-livedspecies that is potentially toxic to cells. This is critical, becausethe pharmacological efficacy of NO depends upon the form in which it isdelivered. In contrast to NO, nitrosonium and nitroxyl do not reactwith O₂ or O₂ ⁻ species, and are also resistant to decomposition in thepresence of redox metals. Consequently, administration of NO equivalentsdoes not result in the generation of toxic by-products or theelimination of the active NO moiety.

Compounds contemplated for use in the invention are nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer nitric oxide to a site of its activity, such as on acell membrane, in vivo. As used here, the term "nitric oxide"encompasses uncharged nitric oxide (NO) and charged nitric oxidespecies, particularly including nitrosonium ion (NO⁺) and nitroxyl ion(NO⁻). The reactive form of nitric oxide can be provided by gaseousnitric oxide. The nitric oxide releasing, delivering or transferringcompounds, having the structure F--NO wherein F is a nitric oxidereleasing, delivering or transferring moiety, include any and all suchcompounds which provide nitric oxide to its intended site of action in aform active for their intended purpose. As used here, the term "NOadducts" encompasses any of such nitric oxide releasing, delivering ortransferring compounds, including, for example, S-nitrosothiols,S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols, sydnonimines,2-hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-(E)-hydroxyimino!-5-nitro-3-hexene amines or amides, nitrosoamines, aswell a subtstates for the endogenous enzymes which synthesize nitricoxide. It is contemplated that any or all of these "NO adducts" can bemono- or poly-nitrosylated or nitrosated at a variety of naturallysusceptible or artificially provided binding sites for nitric oxide orderivatives which donate or release NO.

One group of such NO adducts is the S-nitrosothiols, which are compoundsthat include at least one --S--NO group. Such compounds includeS-nitroso-polypeptides (the term "polypeptide" includes proteins andalso polyamino acids that do not possess an ascertained biologicalfunction, and derivatives thereof); S-nitrosylated amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures and derivatives thereof); S-nitrosylated sugars,S-nitrosylated-modified and unmodified oligonucleotides (preferably ofat least 5, and more particularly 5-200, nucleotides); and anS-nitrosylated hydrocarbons where the hydrocarbon can be a branched orunbranched, and saturated or unsaturated aliphatic hydrocarbon, or anaromatic hydrocarbon; S-nitrosylated hydrocarbons having one or moresubstituent groups in addition to the S-nitroso group; and heterocycliccompounds. S-nitrosothiols and the methods for preparing them aredescribed in U.S. Pat. No. 5,380,758; Oae et al., Org. Prep. Proc. Int.,15(3):165-198 (1983); Loscalzo et al., J. Pharmacol. Exp. Ther.,249(3):726729 (1989) and Kowaluk et al., J. Pharmacol. Exp. Ther.,256:1256-1264 (1990), all of which are incorporated in their entirety byreference.

One particularly preferred embodiment of this aspect relates toS-nitroso amino acids where the nitroso group is linked to a sulfurgroup of a sulfur-containing amino acid or derivative thereof. Forexample, such compounds include the following:S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine,S-nitroso-cysteine and S-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur group on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins, heme proteinssuch as hemoglobin and serum albumin; and biologically protectiveproteins, such as the immunoglobulins and the cytokines. Suchnitrosylated proteins are described in PCT Publ. Applic. No. WO93/09806, published May 27, 1993. Examples include polynitrosylatedalbumin where multiple thiol or other nucleophilic centers in theprotein are modified.

Further examples of suitable S-nitrosothiols include those having thestructures:

(i) CH₃ C(R_(e))(R_(f))!_(x) SNO

wherein x equals 2 to 20 and R_(e) and R_(f) are as defined above;

(ii) HS C((R_(e))(R_(f))!_(x) SNO

wherein x equals 2 to 20; and R_(e) and R_(f) are as defined above;

(iii) ONS C(R_(e))(R_(f))!_(x) B; and

(iv) H₂ N--(CO₂ H)--(CH₂)_(x) --C(O)NH--C(CH₂ SNO)--C(O)NH--CH₂ --CO₂ H

wherein x equals 2 to 20; R_(e) and R_(f) are as defined above; and B isselected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano,carboxamido, cycloalkyl, arylakoxy, alkylsulfinyl, arylthio, alkylamino,dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro andaryl.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) to yield the S-nitrosoderivative. Acids which may be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. Alternatively, the precursorthiol may be nitrosylated by treatment with an alkyl nitrite such astert-butyl nitrite.

Another group of such NO adducts are those wherein the compounds donate,transfer or release nitric oxide and are selected from the groupconsisting of compounds that include at least one ON--N-- or ON--C--group. The compound that includes at least one ON--N-- or ON--C-- groupis preferably selected from the group consisting of ON--N-- orON--C--polypeptides (the term "polypeptide" includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); ON--N-- or ON--C--amino acids(includingnatural and synthetic amino acids and their stereoisomers and racemicmixtures); ON--N-- or ON--C--sugars; ON--N-- or ON--C--modified andunmodified oligonucleotides (preferably of at least 5, and moreparticularly 5-200, nucleotides), ON--O--, ON--N-- orON--C--hydrocarbons which can be branched or unbranched, saturated orunsaturated aliphatic hydrocarbons or aromatic hydrocarbons; ON--N-- orON--C-- hydrocarbons having one or more substituent groups in additionto the ON--N-- or ON--C-- group; and ON--N-- or ON--C--heterocycliccompounds.

Another group of such NO adducts is the nitrites which have an --O--NOgroup wherein the organic template to which the nitrite group isappended is a protein, polypeptide, amino acid, carbohydrate, branchedor unbranched and saturated or unsaturated alkyl, aryl or a heterocycliccompound. A preferred example is the nitrosylated form of isosorbide.Compounds in this group form S-nitrosothiol intermediates in vivo in therecipient human or other animal to be treated and can therefore includeany structurally analogous precursor R--O--NO of the S-nitrosothiolsdescribed above.

Another group of such adducts are nitrates which donate, transfer orrelease nitric oxide and are selected from the group consisting ofcompounds that include at least one at least one O₂ N--O--, O₂ N--N--,O₂ N--S-- or O₂ N--C-- group. Preferred among these are those selectedfrom the group consisting of O₂ N--O--, O₂ N--N--, O₂ N--S-- or O₂N--C--polypeptides; O₂ N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C--aminoacids; O₂ N--O--, O₂ N--N--O₂ N--S-- or O₂ N--C--sugars; O₂ N--O--, O₂N--N--, O₂ N--S-- or O₂ N--C--modified and unmodified oligonucleotides;O₂ N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C-- hydrocarbons which can bebranched or unbranched, saturated or unsaturated aliphatic hydrocarbonsor aromatic hydrocarbons; O₂ N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C--hydrocarbons having one or more substituent groups in addition to the O₂N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C--group; and O₂ N--O--, O₂N--N--, O₂ N--S-- or O₂ N--C--heterocyclic compounds. Preferred examplesare isosorbide dinitrate and isosorbide mononitrate.

Another group of such NO adducts is the nitroso-metal compounds whichhave the structure (R)_(v) --A--M--(NO)_(v). R includes polypeptides(the term "polypeptide" includes proteins and also polyamino acids thatdo not possess an ascertained biological function, and derivativesthereof); amino acids (including natural and synthetic amino acids andtheir stereoisomers and racemic mixtures and derivatives thereof);sugars; modified and unmodified oligonucleotides (preferably of at least5, and more particularly 5-200, nucleotides); and a hydrocarbon wherethe hydrocarbon can be a branched or unbranched, and saturated orunsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon;hydrocarbons having one or more substituent groups in addition to theAnitroso group; and heterocyclic compounds. A is S, O, or N, v is aninteger independently selected from 1, 2 and 3, and M is a metal,preferably a transition metal. Preferred metals include iron, copper,manganese, cobalt, selenium and luthidium. Also contemplated areN-nitrosylated metal centers such as nitroprusside.

Another group of such adducts are N-oxo-N-nitrosoamines which donate,transfer or release nitric oxide and have a R₁ R₂ --N(O--M⁺)--NO groupwherein R₁ and R₂ include polypeptides, amino acids, sugars, modifiedand unmodified oligonucleotides, hydrocarbons where the hydrocarbon canbe a branched or unbranched, and saturated or unsaturated aliphatichydrocarbon or an aromatic hydrocarbon, hydrocarbons having one or moresubstituent groups and heterocyclic compounds. M⁺ is a metal cation,such as, for example, a Group I metal cation.

Another group of such adducts are thionitrates which donate, transfer orrelease nitric oxide and have the structure R₁₀ --S--NO₂ wherein R₁₀includes polypeptides, amino acids, sugars, modified and unmodifiedoligonucleotides, and a hydrocarbon where the hydrocarbon can be abranched or unbranched, and saturated or unsaturated aliphatichydrocarbon or an aromatic hydrocarbon.

Agents which stimulate endogenous NO synthesis such as L-arginine, thesubstrate for nitric oxide synthase, are also suitable for use inaccordance with the invention.

When administered in vivo, the nitric oxide may be administered incombination with pharmaceutical carriers and in dosages describedherein.

In another aspect the invention provides a method of treating maleimpotence in an individual in need thereof by administering to theindividual a therapeutically effective amount of a compositioncomprising a nitrosated or nitrosylated α-antagonist of the invention ina pharmaceutically acceptable carrier.

In another aspect the invention provides a method of treating maleimpotence in an individual in need thereof which comprises treating anindividual for male impotence by administering to the individual atherapeutically effective amount of a composition comprising anα-adrenergic receptor antagonist (α-antagonist), which can optionally besubstituted with at least one NO or NO₂ moiety, and a compound thatdonates, transfers or releases nitric oxide in a pharmaceuticallyacceptable carrier.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from about 1 to about 100 mg/kg body weightdaily and more usually about 3 to 30 mg/kg. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. Topical administration may also involve the useof transdermal administration such as transdermal patches oriontophoresis devices. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1, 3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed an a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. in addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, granules and gels. In such solid dosage forms,the active compound may be admixed with at least one inert diluent suchas sucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds which are known to be effective against thespecific disease state that one is targeting for treatment. Thecompositions of the invention can be administered as a mixture of anα-antagonist and a nitric oxide donor, they can also be used incombination with one or more compounds which are known to be effectiveagainst the specific disease state that one is targeting for treatment.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

EXAMPLE 1 N-(N-L-γ-glutamyl-S-Nitros-L-cysteinyl)glycine

N-(N-L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolvedin deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperatureand then the reaction mixture was cooled to 0° C. With rapid stirring, asolution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) wasadded. Stirring with cooling of the reaction mixture was continued forapproximately 1 hour after which time the pink precipitate which formedwas collected by vacuum filtration. The filter cake was resuspended inchilled 40% acetone-water (600 ml) and collected by vacuum filtration.The filter cake was washed with acetone (2×200 ml) and ether (100 ml)and then dried under high vacuum at room temperature in the dark toafford the title compound as a pink powder. ¹ H NMR (D₂ O)δ:1.98 (m,2H), 2.32 (t, 2H), 3.67 (t, 1H), 3.82 (s 2H), 3.86 (dd, 1H), 3.98 (dd,1H), 4.53 (m, 1H).

EXAMPLE 22-Acyl-17α(3-methyl-3-nitrosothiolbutoxy)yohimban-16α-carboxylic acidmethyl ester hydrochloride salt

2a. 3-Methyl-3(2-tetrahydropyranyl)thiobutyric acid

3-Methyl-3-thiobutyric acid (4.2 g, 31 mmol), dihydropyran (2.8 ml, 31mmol), and 200 μl of 4 N HCl/Et₂ O were allowed to stand at roomtemperature overnight. The volatiles were evaporated in vacuo (2 mm Hg)yielding 6.6 g (30 mmol) of material which was used without furtherpurification. ¹ H-NMR (CDCl₃):δ 4.92 (d, J=8.1 Hz, 1H), 4.09 (d, J=10.5Hz, 1H), 3.49-3.56 (mult, 1H), 2.73 (dd, J=1.2 and 13.7 Hz, Hz, 1H),2.64 (d, J=13.8 Hz, 1H), 1.84-1.89 (mult 2H), 1.55-1.69 (mult, 4H),1.51(s, 3H), 1.42 (s, 3H).

2b. 3,3'-Methyl-3,3'(2-tetrahydropyranyl)thiobutyric acid anhydride

The product of Example 2a (1.1 g, 5 mmol) and triethylamine (710 μl, 5mmol) was dissolved in ethyl acetate (50 ml) and cooled to 0° C.Triphosgene (250 mg, 0.85 mmol) was added all in one portion and thereaction was stirred at 0° C. for 15 minutes then warmed to roomtemperature with continued stirring for 30 min. The precipitate whichformed was removed by filtration and the filtrate was concentrated byrotary evaporation to afford 1.0 g (5 mmol) of the title compound. ¹H-NMR (CDCl₃):δ 5.03-5.06 (mult, 2H), 4.04-4.08 (mult, 2H), 3.46-3.51(mult, 2H), 2.89 (d, J=15.7 Hz, 2H), 2.77 (d, J=15.6 Hz, 2H), 1.79-1.88(mult, 4H), 1.51-1.67 (mult, 8H), 1.54 (s, 6H), 1.49 (s, 6H).

2c. 17α (3-methyl-3-tetrahydropyranylthiolbutoxy)yohimban-16α-carboxylicacid methyl ester

To a solution of yohimbine (1.6 g, 4.5 mmol) in pyridine (6 ml) wasadded the product of Example 2b (2.5 g, 6 mmol) and4-dimethylaminopyridine (730 mg, 6 mmol). The reaction mixture wasstirred at room temperature for 6 days. Acetonitrile (50 ml) was addedto the reaction and then all of the volatile components were evaporatedin vacuo. The residue was dissolved in ethyl acetate (100 ml) and washedwith a 10% solution of aqueous sodium carbonate. The aqueous wash wasthen back extracted once with ethyl acetate. The combined organicextracts were washed with H₂ O, brine, and then dried over anhydroussodium sulfate. Treatment of the solution with activated charcoalfollowed by filtration and concentration of the filtrate in vacuo gave2.8 g of a dark syrup.

Chromatography on silica gel eluting with 1:1 hexane/ethyl acetatecontaining 1% by volume triethylamine afforded 670 mg (20%) of the titlecompound. ¹ H-NMR (CDCl₃):δ 7.76 (s, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.29(dd, J=1.0 and 7.0 Hz, 1H), 7.12 (ddd; J=1.3, 7.1, and 7.1 Hz; 1H), 7.07(ddd; J=1.1, 7.2, and 7.2 Hz; 1H), 5.46 (d, J=2.6 Hz, 1H), 5.07-5.11(mult, 1H), 4.06-4.11 (mult, 1H), 3.69 (s, 3H), 3.47-3.55 (mult, 1H),3.39 (d, J=10.4 Hz, 1H), 3.02-3.12 (mult, 2H), 2.97 (dd, J=4.5 and 12.2Hz, 1H), 2.80 (d, J=14.3 Hz, 1H), 2.71 (mult, 1H), 2.69 (d, J=13.2 Hz,1H), 2.61-2.65 (mult, 1H), 2.39 (dd, J=2.6 and 11.6 Hz, 1H), 2.23-2.33(mult, 2H), 1.71-2.07 (mult, 5H), 1.58-1.69 (mult, 8H), 1.51 (s, 3H),1.49 (s, 3H).

Anal Calcd for (C₃₁ H₄₂ N₂ O5S-1/2 H₂ O): C, 66.05; H, 7.69; N, 4.97; S,5.69. Found C, 65.74; H, 7.33; N, 4.88; S, 5.57.

2d. 2-Acyl-17α(3-methyl-3-thiolbutoxy)yohimban-16α-carboxylic acidmethyl ester

The product of Example 2c (620 mg, 1.1 mmol) was refluxed in a mixtureof acetic acid (5 ml) and acetyl chloride (5 ml) for 4 hours. Thesolvent was evaporated in vacuo (2 mm Hg). The residue was partitionedbetween 5% aqueous ammonium hydroxide and ethyl acetate. The aqueouswash was extracted with ethyl acetate. The combined organic extractswere washed with brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated in vacuo and the residue was chromatographed onsilica gel eluting with 1:1 hexane/ethyl acetate containing 1% by volumetriethylamine to afford 210 mg (34%) of2-acyl-17u.(3-methyl-3-thioacetylbutoxy)yohimban-16 α-carboxylic acidmethyl ester. This diacetate (180 mg, 0.32 mmol) was dissolved in aceticacid (4 ml) to which was added mercuric trifluoroacetate (190 mg, 0.45mmol) and the reaction mixture was stirred at room temperature for 2hours. The volatiles were evaporated in vacuo leaving a gum which wastriturated with IN HCl (6 ml) to afford a yellow powder. The powder waspartitioned between ethyl acetate and 10% aqueous ammonium hydroxide.The organic phase was filtered through Celite to remove the gray solidwhich was present and then the filtrate was washed with brine and thendried over anhydrous sodium sulfate.

Evaporation of the volatiles in vacuo afforded a solid which waschromatographed on silica gel eluting with a gradient of with 1:1hexane/ethyl acetate containing 1% by volume triethylamine to ethylacetate containing 1% by volume triethylamine to yield 60 mg (37%) ofthe title compound as a white powder. ¹ H-NMR (CDCl₃):δ 7.81 (d, J=7.0Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.23-7.29 (mult, 2H), 5.46 (s, 1H),4.17 (d, J=9.9 Hz, 1H), 3.64 (s, 3H), 3.11-3.15 (mult, 1H), 3.00 (dd,J=3.5 and 12.4 Hz, 1H), 2.64-2.84 (mult, 10H), 2.31 (dd, J=2.6 and 11.7Hz, 1H), 2.24 (d, J=12.7 Hz, 1H), 2.04-2.08 (mult, 2H), 1.41-1.62 (mult,11H). ¹³ C-NMR (CDCl₃):δ 171.6, 170.7, 169.5, 13 7.3, 136.4, 129.6,124.1, 122.9, 118.3, 117.2, 114.6, 70.0, 61.0, 59.8, 51.9, 51.8, 50.9,47.7, 45.6, 37.8, 37.6, 36.22, 36.2, 33.2, 29.9, 27.1, 23.8, 22.3.

2e. 2-Acyl-17α(3-methyl-3-nitrosothiolbutoxy)yohimban-16α-carboxylicacid methyl ester hydrochloride salt

To a slurry of the compound of Example 2d (40 mg, 0.078 mmol) in 1:1methanol/IN HCI (4 ML) with dimethylformamide (400 μl) was added asolution of sodium nitrite (11 mg, 0.16 mmol) in H₂ O (200 μl). Thewhite powder turned green as the slurry was stirred at room temperaturefor 25 minutes. At this juncture dimethylformamide (600 μl) andadditional aqueous sodium nitrite (11 mg in 200 μl of H₂ O) was addedand stirring at room temperature was continued for an additional 15minutes. The reaction mixture was partitioned between CHCl₃ and H₂ Oadding 10% aqueous ammonium hydroxide to the aqueous phase until basicto pH paper. The aqueous layer was extracted with CHCl₃ and the combinedorganic extracts were washed with brine and then dried over anhydroussodium sulfate. The volatiles were evaporated in vacuo and the residuewas dissolved in ether. The product was precipitated with ethereal HClto afford 19 mg of the title compound as a green solid. ¹ H-NMR(CDCl₃):δ 7.81 (dd, J=1.7 and 6.8 Hz, 1H), 7.42 (d, J=6.8 Hz, 1H),7.23-7.29 (mult, 2H), 5.43 (d, J=2.6 Hz, 1 H), 4.15 (d, J=9.8 Hz, 1H),3.63 (s, 3H), 3.36 (d, J=15.1 Hz, 1H), 3.30 (d, J=15.1 Hz, 1H), 3.12(dd, J=4.9 and 11.0 Hz, 1H), 3.00 (dd, J=3.7 and 12.3 Hz, 1H), 2.72 (s,3H), 2.63-2.82 (mult, 3H), 2.31 (dd, J=2.6 and 11.7 Hz, 1H), 2.03 (s,3H), 2.00 (s, 3H), 1.0-2.0 (mult, 9H).

EXAMPLE 3 In Vivo Comparative Erectile Responses

Male New Zealand white rabbits weighing 2.5 kg were used as the animalmodel. Animals were first relaxed with an i.m. injection of 25 mg/kgketamine prior to anesthesia with a bolus i.v. injection of 10 mg/kgProfol and maintained with i.v. infusion at 0.5 mg/kg/min. Ventilationof the animals was performed with 1% halothane plus 0.8 L/min O₂ and 1L/min N₂ O. A 22 gauge angiocatheter was placed in the femoral arteryfor measurement of systemic blood pressure. A dorsal incision was madein the penis and the corpora cavernosa exposed and cannulated with a 21gauge butterfly needle to measure intracavernosal pressure.

Drugs at various concentrations were delivered intracavernosally at avolume of 150 μl through a 25 gauge needle. A 150 μl solution of amixture of papaverine (30 mg/kg), phentolamine (1 mg/kg) andprostaglandin E1 (10 μg/ml) (pap/phent/PGE1) was injected in the corporaas a standard solution for comparison with the response of yohimbine,Example 1, Example 2, and the combination of yohimbine and Example 1.This pap/phent/PGE1 mixture is considered to cause a maximalerection-inducing effect.

As shown in FIG. 1, yohimbine dose dependently induced erectile responsein the anesthetized rabbit. A 500 μg dose of Example 1 was able toinduce near maximal response relative to the standard dose ofpap/phent/PGE1. A combination of the submaximal dose of yohimbine(150μg) and Example 1 (500 μg) also induced maximum erectile response.Yohimbine at both the submaximal and maximal efficacy doses producedvery short duration of action (FIG. 2). Example 1 produced a much longerduration of action. The duration of action is potentiated by acombination of Example 1 and yohimbine which is longer than the sum ofthe duration of each of these compounds alone (FIG. 2).

FIG. 3 shows that Example 2 at the 500 μg dose is equipotent to thestandard dose of pap/phent/PGE 1. A higher dose of Example 2 (1 mg) isat least equal to or more efficacious that the standard dose of thepap/phent/PGE1 mixture. FIG. 4 shows that Example 2 has the advantage ofproducing longer duration of action compared to yohimbine. FIG. 5demonstrates that a dose (500 μg) of Example 2 effective in the erectileresponse did not produce any effect on systemic blood pressure uponintracavernosal injection. However, a standard dose of the mixture ofpap/phent/PGE1 produced a significant decrease in systemic bloodpressure upon intracavernosal injection, suggesting that Example 2 lacksthis side effect.

FIG. 1 shows the percent peak erectile response in vivo compared to thatproduced by 150 μl of pap/phent/PGE1 (30 mg/ml: 1 mg/ml: 10 μg/ml) inthe anesthetized rabbit following the intracavernosal injection of 150μl of yohimbine (150 μg, 500 μg), Example 1 (500 μg), and a combinationof yohimbine (150 μg) and Example 1 (500 μg). The ordinate is thepercent response of intracavernosal pressure relative to that producedby pap/phent/PGE1 and the abscissa indicates the various drugs given.

FIG. 2 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg), Example 1 (500 μg), and a combination of yohimbine(150 μg) and Example 1 (500 μg). The ordinate indicates the variousdrugs given and the abscissa is the duration in minutes.

FIG. 3 shows the percent peak erectile response in vivo compared to thatproduced by 150 til of pap/phent/PGE1 (30 mg/ml: 1 mg/ml: 10 μg/ml) inthe anesthetized rabbit following the intracavemosal injection of 150 glof yohimbine (150 μg, 500 μg and 1 mg) and Example 2 (500 μg, 1 mg). Theordinate is the percent response of intracavernosal pressure relative tothat produced by pap/phent/PGE1 and the abscissa indicates the variousdoses of yohimbine and Example 2 given.

FIG. 4 shows the duration of the erectile response in vivo in theanesthetized rabbit upon intracavernosal administration of yohimbine(150 μg, 500 μg and 1 mg) and Example 2 (500 μg and 1 mg). The ordinateindicates the various doses of yohimbine and Example 2 given and theabscissa is the duration in minutes.

FIGS. 5A and 5B compare the effects of intracavernosal injections ofExample 2 (500 μg) and the standard mixture of pap/phent/PGE1 onsystemic blood pressure in the anesthetized rabbit.

What is claimed is:
 1. A nitrosated or nitrosylated α-adrenergicreceptor antagonist which is a compound having the structure: ##STR33##wherein R_(h) is hydrogen, --C(O)--OR_(d) or --C(O)--X wherein X is (1)--Y--(C(R_(e))(R_(f)))_(p) --G--(C(R_(e))(R_(f)))_(p) --T--Q; wherein Gis (i) a covalent bond; (ii) --T--C(O)--; (iii) --C(O)--T--; or (iv)--C(Y--C(O)--R_(m))-- wherein R_(m) is a mono- or bi-cyclic ring systemcontaining one or two aromatic rings and comprising at least onenitrogen, oxygen or sulfur atom in at least one aromatic ring, and thatis unsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalky, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo and nitro, or R_(m) is a 3-, 4-,5-, 6-, or 7-membered non-aromatic ring containing at least one nitrogenatom, oxygen, or sulfur atom; Y is oxygen, sulfur, or NR_(i) in whichR_(i) is hydrogen or lower alkyl; R_(d) is hydrogen, lower alkyl, orcycloalkyl, or R_(d) is a mono- or bi-cyclic carbocyclic ring systemhaving one or two aromatic rings which is unsubstituted or substitutedwith one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy,halo, and nitro, or R_(d) is a mono- or bi-cyclic ring system containingone or two aromatic rings and comprising at least one nitrogen, oxygenor sulfur atom in at least one aromatic ring, and is unsubstituted orsubstituted with one, two or three substituents independently selectedfrom lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro; R_(e) and R_(f) are independently selected fromhydrogen, lower alkyl, cycloalkyl, alkylamino and dialkylamino, or R_(e)and R_(f) are independently selected from a mono- or bi-cycliccarbocyclic ring system having one or two aromatic rings which isunsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, and nitro, or R_(e) and R_(f)are independently selected from a mono- or bi-cyclic ring systemcontaining one or two aromatic rings and comprising at least onenitrogen, oxygen or sulfur atom in at least one aromatic ring, and thatis unsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo and nitro, or R_(e) and R_(f)are independently a lower alkyl appended to a mono- or bi-cyclic ringsystem having one or two aromatic rings that is unsubstituted orsubstituted with one, two or three substituents indpendently selectedfrom lower alkyl, halo alkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro, or R_(e) and R_(f) taken together are carbonyl,cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is acovalent bond, oxygen, sulfur or nitrogen and Q is --NO or --NO₂ ; or(2) ##STR34## wherein W is a 3-, 4-, 5-, 6-, or 7-membered non-aromaticring containing at least one nitrogen atom, oxygen, or sulfur atom, or Wis NR_(i) R'_(i) wherein R_(i) and R'_(i) are independently selectedfrom lower alkyl and alkenyl, or R_(i) or R'_(i) are independentlyselected from a mono- or bi-cyclic carbocyclic ring system having one ortwo aromatic rings which may be unsubstituted or substituted with one,two or three substituents independently selected from lower alkyl,haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, andnitro; and wherein R_(j) is --D or --(O)CR_(d), and D is (i) --NO, (ii)--NO₂ ; (iii) --C(R_(d))--O--C(O)--Y--(C(R_(e))(R_(f)))_(p) --T--Q inwhich R_(d), Y, R_(e), R_(f), p, T and Q are as defined above; (iv)--(CO)--T¹ --(C(R_(e))(R_(f)))_(p) --T² --Q wherein T¹ and T² areindependently selected from T, and R_(e), R_(f), p and T are definedabove; or (v) --C(O)--T(C(R_(y))(R_(z)))_(p) wherein R_(y) and R_(z) areindependently selected from --T¹ --(C(R_(e))(R_(f)))_(p)--G--(C(R_(e))(R_(f)))_(p) --T² --Q wherein G, R_(d), R_(e), R_(f), p Qand T are as defined above.
 2. The compound of claim 1 wherein theα-adrenergic receptor antagonist is a compound which has been nitrosatedor nitrosylated through a site selected from the group consisting ofoxygen, sulfur, carbon and nitrogen.
 3. A compound according to claim 1,wherein(a) the mono- or bicyclic ring system having one or two aromaticrings is a member selected from the group consisting of phenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl, each group of which canbe unsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, and nitro or may betetrafluorophenyl and pentafluorophenyl; and (b) the mono- or bi-cyclicring system containing one or two aromatic rings and comprising at leastone nitrogen, oxygen or sulfur atom in at least one aromatic ring is amember selected from the group consisting of pyridine, pyrazine,pyrimidine, pyridazine, pyrazole, triazole, thiazole, isothiazole,benzothiazole, benzoxazole, thiadiazole, oxazole, pyrrole, imidazole andisoxazole, each group of which can be unsubstituted or substituted withone, two or three substituents independently selected from lower alkyl,haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo andnitro.
 4. A compound according to claim 1, wherein said compound is amember selected from the group consisting of 2-acyl-17α(3-methyl-3-nitrosothiolbutoxy) yohimban-16α-carboxylic acid C₁ -C₄alkyl ester and acid addition salts thereof.
 5. A composition comprisingthe nitrosated or nitrosylated α-adrenergic receptor antagonist of claim1 and a pharmaceutically acceptable carrier.
 6. A method of treatingmale impotence in an individual in need thereof which comprises treatingan individual for male impotence by administering to the individual atherapeutically effective amount of at least one compound according toclaim 1 in a pharmaceutically acceptable carrier.
 7. A compositioncomprising (i) a therapeutically effective amount of at least onenitrosated or nitrosylated α-adrenergic receptor antagonist compoundaccording to claim 1 and (ii) a S-nitrosothiol compound, wherein theS-nitrosothiol compound donates, transfers or releases nitric oxide orelevates endogenous synthesis levels of nitric oxide.
 8. The compositionof claim 7 wherein the nitrosated or nitrosylated α-adrenergic receptorantagonist compound is a nitrosated or nitrosylated member selected fromthe group consisting of yohimbine β-yohimbine, yohimbol, pseudoyohimbineand epi-3α-yohimbine.
 9. The composition according to claim 7 whereinsaid S-nitrosothiol compound is S-nitroso-N-acetylcysteineS-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, orS-nitroso-glutathione.
 10. The composition of claim 7 wherein theS-nitrosothiol is:(i) CH₃ (C(R_(e))(R_(f)))_(x) SNO; (ii)HS(C(R_(e))(R_(f)))_(x) SNO; (iii) ONS(C(R_(e))(R_(f)))_(x) B; or (iv)H₂ N--(CO₂ H)--(CH_(s))_(x) --C(O)NH--C(CH₂ SNO)--C(O)NH--CH₂ --CO₂Hwherein x equals 2 to 20; R_(e) and R_(f) are independently selectedfrom hydrogen, lower alkyl, cycloalkyl, alkylamino and dialkylamino, orR_(e) and R_(f) are independently selected from a mono- or bi-cycliccarbocyclic ring system having one or two aromatic rings which isunsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, and nitro, or R_(e) and R_(f)are independently selected from a mono- or bi-cyclic ring systemcontaining one or two aromatic rings and comprising at least onenitrogen, oxygen or sulfur atom in at least one aromatic ring, and thatis unsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo and nitro, or R_(e) and R_(f)are independently a lower alkyl appended to a mono- or bi-cyclic ringsystem having one or two aromatic rings that is unsubstituted orsubstituted with one, two or three substituents indpendently selectedfrom lower alkyl, halo alkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro, or R_(e) and R_(f) taken together are carbonyl,cycloalkyl or bridged cycloalkyl; and B is selected from the groupconsisting of fluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylkoxywherein the aryl group is a mono- or bi-cyclic carbocyclic ring systemhaving one or two aromatic rings, alkylsulfinyl, arylthio wherein thearyl group is a mono- or bi-cyclic carbocyclic ring system having one ortwo aromatic rings, alkylamino, dialkylamino, hydroxy, carbamoyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl,hydrogen, nitro and a mono- or bi-cyclic carbocyclic ring system havingone or two aromatic rings.
 11. A method of treating male impotence in anindividual in need thereof which comprises treating an individual formale impotence by administering to the individual a therapeuticallyeffective amount of a composition according to claim 7 in apharmaceutically acceptable carrier.
 12. A composition comprising (i) atherapeutically effective amount of at least one nitrosated ornitrosylated α-adrenergic receptor antagonist compound according toclaim 1 and (ii) a compound that donates, transfers or releases nitricoxide or elevates endogenous synthesis levels of nitric oxide, whereinthe compound that donates, transfers or releases nitric oxide orelevates endogenous synthesis levels of nitric oxide is selected fromthe group consisting of:(i) compounds that include at least one ON--O--,ON--N-- or ON--C-- group; (ii) a N-oxo-N-nitrosoamine which has an R₁ R₂--N(O--M⁺)--NO group, wherein M⁺ is a metal cation, and R₁ and R₂independently include polypeptides, amino acids, sugars,oligonucleotides, a branched or unbranched, saturated or unsaturatedaliphatic hydrocarbon, a mono- or bicyclic carbocyclic ring systemhaving one or two aromatic rings, hydrocarbons having one or moresubstituent groups, a heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring, or a heterocyclic compound which is a 3-, 4-, 5-, 6-, or7-membered non-aromatic ring containing at least one nitrogen atom,oxygen, or sulfur atom; (iii) a thionitrate which has the structure R₁₀--S--NO₂ wherein R₁₀ includes polypeptides, amino acids, sugars,oligonucleotides, a branched or unbranched, saturated or unsaturatedaliphatic hydrocarbon or a mono- or bicyclic carbocyclic ring systemhaving one or two aromatic rings; and (iv) a nitrate which has thestructure R₁₀ --O--NO₂ wherein R₁₀ is as defined above.
 13. Thecomposition of claim 12 wherein the nitrosated or nitrosylatedα-adrenergic receptor antagonist is a nitrosated or nitrosylated memberselected from the group consisting of yohimbine, β-yohimbine, yohimbol,pseudoyohimbine and epi-3α-yohimbine.
 14. The composition of claim 12,wherein the compounds that include at least one ON--O--, ON--N-- orON--C-- group are selected from the group consisting of aON--N--polypeptide, an ON--C--polypeptide, an ON--N--amino acid, anON--C--amino acid, an ON--13 sugar, an ON--C--sugar, anON--N--oligonucleotide, an ON--C--oligonucleotide, a straight orbranched, saturated or unsaturated, substituted or unsubstituted,aliphatic or aromatic ON--N--hydrocarbon, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON--C--hydrocarbon, a straight or branched, saturated orunsaturated, aliphatic or aromatic ON--O--hydrocarbon, aON--N--heterocyclic compound which is a mono- or bi-cyclic ring systemcontaining one or two aromatic rings and comprising at least onenitrogen, oxygen or sulfur atom in at least one aromatic ring or aheterocyclic compound which is a 3-, 4-, 5-, 6-, or 7-memberednon-aromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom, and a ON--C--heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring or a heterocyclic compound which is a 3-, 4-, 5-, 6-, or7-membered non-aromatic ring containing at least one nitrogen atom,oxygen, or sulfur atom.
 15. A method of treating male impotence in anindividual in need thereof comprising treating the individual for maleimpotence by administering to the individual a therapeutically effectiveamount of at least one compound according to claim 12 in apharmaceutically acceptable carrier.
 16. A composition comprising (i)the nitrosated or nitrosylated α-adrenergic receptor antagonist of claim1 and (ii) L-arginine.
 17. A method of treating male impotence in anindividual in need thereof comprising treating the individual for maleimpotence by administering to the individual a therapeutically effectiveamount of at least one composition according to claim 16 in apharmaceutically acceptable carrier.
 18. A composition comprising (i)the nitrosated or nitrosylated α-adrenergic receptor antagonist of claim1 and (ii) a compound that donates, transfers or releases nitric oxideor elevates endogenous synthesis levels of nitric oxide, wherein thecompound that donates, transfers or releases nitric oxide or elevatesendogenous synthesis levels of nitric oxide is a compound comprising atleast one O₂ N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C-- group.
 19. Thecomposition of claim 18, wherein the compound comprising at least one O₂N--O--, O₂ N--N--, O₂ N--S-- or O₂ N--C-- group is an O₂N--O--polypeptide, an O₂ N--N--polypeptide, an O₂ N--S--polypeptide, anO₂ N--C--polypeptide, an O₂ N--O--amino acid, an O₂ N--N--amino acid, anO₂ N--S--amino acid, an O₂ N--C--amino acid, an O₂ N--O--sugar, an O₂N--N--sugar, an O₂ N--S--sugar, an O₂ N--C--sugar, an O₂N--O--oligonucleotide, an O₂ N--N--oligonucleotide, an O₂N--S--oligonucleotide, an O₂ N--C--oligonucleotide, a straight orbranched, saturated or unsaturated, substituted or unsubstituted,aliphatic or aromatic O₂ N--O--hydrocarbon, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic O₂ N--N--hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromatic O₂N--S--hydrocarbon, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic O₂N--C--hydrocarbon, an O₂ N--O--heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring or a compound which is a 3-, 4-, 5-, 6-, or 7-memberednon-aromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom, an O₂ N--N--heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring or a compound which is a 3-, 4-, 5-, 6-, or 7-memberednon-aromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom, an O₂ N--S--heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring or a compound which is a 3-, 4-, 5-, 6-, or 7-memberednon-aromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom or an O₂ N--C--heterocyclic compound which is a mono- orbi-cyclic ring system containing one or two aromatic rings andcomprising at least one nitrogen, oxygen or sulfur atom in at least onearomatic ring or a compound which is a 3-, 4-, 5-, 6-, or 7-memberednon-aromatic ring containing at least one nitrogen atom, oxygen, orsulfur atom.
 20. A method of treating male impotence in an individual inneed thereof comprising treating the individual for male impotence byadministering to the individual a therapeutically effective amount of atleast one composition according to claim 18 in a pharmaceuticallyacceptable carrier.